Identification of proteasome and caspase inhibitors targeting SARS-CoV-2 Mpro.
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ABSTRACT:
SUBMITTER: Wang Z
PROVIDER: S-EPMC8166895 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication and essential for viral life cycle, has been established as an essential drug discovery target for SARS-CoV-2. Herein, we employed computationally screening of Druglib database containing FDA approved drugs against active pocket of SARS-CoV-2 Mpro using MTiopen screen web server, yields a total of 1051 FDA approved drugs with docking energy >-7 kcal/mol. The top 10 screened potential compounds against SARS-CoV-2 Mpro were then studied by re-docking, binding affinity, intermolecular interaction, and complex stability via 100 ns all atoms molecular dynamics (MD) simulation followed by post-simulation analysis, including end point binding free energy, essential dynamics, and residual correlation analysis against native crystal structure ligand N3 inhibitor. Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 Mpro revealed R428 (-10.5 kcal/mol), Teniposide (-9.8 kcal/mol), VS-5584 (-9.4 kcal/mol), and Setileuton (-8.5 kcal/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.
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Project description:The continual spread of novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), posing a severe threat to the health worldwide. The main protease (Mpro, alias 3CLpro) of SARS-CoV-2 is a crucial enzyme for the maturation of viral particles and is a very attractive target for designing drugs to treat COVID-19. Here, we propose a multiple conformation-based virtual screening strategy to discover inhibitors that can target SARS-CoV-2 Mpro. Based on this strategy, nine Mpro structures and a protein mimetics library with 8960 commercially available compounds were prepared to carry out ensemble docking for the first time. Five of the nine structures are apo forms presented in different conformations, whereas the other four structures are holo forms complexed with different ligands. The surface plasmon resonance assay revealed that 6 out of 49 compounds had the ability to bind to SARS-CoV-2 Mpro. The fluorescence resonance energy transfer experiment showed that the biochemical half-maximal inhibitory concentration (IC50) values of the six compounds could hamper Mpro activities ranged from 0.69 ± 0.05 to 2.05 ± 0.92 μM. Evaluation of antiviral activity using the cell-based assay indicated that two compounds (Z1244904919 and Z1759961356) could strongly inhibit the cytopathic effect and reduce replication of the living virus in Vero E6 cells with the half-maximal effective concentrations (EC50) of 4.98 ± 1.83 and 8.52 ± 0.92 μM, respectively. The mechanism of the action for the two inhibitors were further elucidated at the molecular level by molecular dynamics simulation and subsequent binding free energy analysis. As a result, the discovered noncovalent reversible inhibitors with novel scaffolds are promising antiviral drug candidates, which may be used to develop the treatment of COVID-19.
| S-EPMC8315252 | biostudies-literature
Project description:Since the outbreak of COVID-19, the pandemic caused by SARS-CoV-2 infection is still spreading at an alarming rate and has caused huge loss of life and economic damage worldwide. Although more than one year has passed, effective treatments for COVID-19 and other pathogenic coronaviruses have not yet been developed. Therefore, the development of SARS-CoV-2 inhibitors is an urgent priority. Given that the Mpro sequences of SARS-CoV-2 and SARS-CoV-1 are 100% identical in the catalytic domain for protein cleavage, the viral main protease (Mpro) is one of the most extensive drug targets in all the drug targets being investigated for SARS-CoV-2. To provide scientific researchers with timely anti-SARS-CoV drug development information for Mpro, we focus on the past and current drug design and development strategies for MPro in this review. We believe that this review will provide meaningful guidance for the design and development of innovative drugs against COVID-19 and other pathogenic coronaviruses in the future.
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Project description:COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro's active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.
| S-EPMC9958325 | biostudies-literature
Project description: Not available
| S-EPMC7450161 | biostudies-literature
Project description:The recent outbreak of COVID-19, caused by the novel pathogen SARS-coronavirus 2 (SARS-CoV-2) is a severe health emergency. In this pandemic, drug repurposing seems to be the most promising alternative to identify effective therapeutic agents for immediate treatment of infected patients. The present study aimed to evaluate all the drugs present in drug bank as potential novel SARS-CoV-2 inhibitors, using computational drug repurposing studies. Docking-based virtual screening and binding energy prediction were performed, followed by Absorption Distribution Metabolism Excretion calculation. Hydroxychloroquine and Nelfinavir have been identified as the best potential inhibitor against the SARS-CoV-2, therefore, they were used as reference compounds in computational DR studies. The docking study revealed 13 best compounds based on their highest binding affinity, binding energy, and dock score concerning the other screened compounds. Out of 13, only 4 compounds were further shortlisted based on their binding energy and best ADME properties. The hierarchical virtual screening yielded the best 04 drugs, DB07042 (compound 2), DB13035 (compound 3), DB13604 (compound 5) and DB08253 (compound 6), with commendable binding energies in kcal/mol, i.e. -65.45, -62.01, -52.09 and -51.70 respectively. Further, Molecular dynamics simulation with 04 best-retrieved hits has confirmed stable trajectories in protein in terms of root mean square deviation and root mean square fluctuation. During 30 ns simulation, the interactions were also found similar to the docking-based studies. However, clinical studies are necessary to investigate their therapeutic use against this outbreak.
| S-EPMC8483991 | biostudies-literature
Project description:The COVID-19 pandemic is an ongoing global health emergency caused by a newly discovered coronavirus SARS-CoV-2. The entire scientific community across the globe is working diligently to tackle this unprecedented challenge. In silico studies have played a crucial role in the current situation by expediting the process of identification of novel potential chemotypes targeting the viral receptors. In this study, we have made efforts to identify molecules that can potentially inhibit the SARS-CoV-2 main protease (Mpro) using the high-resolution crystal structure of SARS-CoV-2 Mpro. The SARS-CoV-2 Mpro has a large flexible binding pocket that can accommodate various chemically diverse ligands but a complete occupation of the binding cavity is necessary for efficient inhibition and stability. We augmented glide three-tier molecular docking protocol with water thermodynamics to screen molecules obtained from three different compound libraries. The diverse hits obtained through docking studies were scored against generated WaterMap to enrich the quality of results. Five molecules were selected from each compound library on the basis of scores and protein-ligand complementarity. Further MD simulations on the proposed molecules affirm the stability of these molecules in the complex. MM-GBSA results and intermolecular hydrogen bond analysis also confirm the thermodynamic stability of proposed molecules. This study also presumably steers the structure determination of many ligand-main protease complexes using x-ray diffraction methods.Communicated by Ramaswamy H. Sarma.
| S-EPMC7876914 | biostudies-literature
Project description:There is an urgent need to develop effective treatments for coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid spread of SARS-CoV-2 has resulted in a global pandemic that has not only affected the daily lives of individuals but also had a significant impact on the global economy and public health. Although extensive research has been conducted to identify inhibitors targeting SARS-CoV-2, there are still no effective treatment strategies to combat COVID-19. SARS-CoV-2 comprises two important proteolytic enzymes, namely, the papain-like proteinase, located within non-structural protein 3 (nsp3), and nsp5, both of which cleave large replicase polypeptides into multiple fragments that are required for viral replication. Moreover, a domain within nsp3, known as the macrodomain (Mac1), also plays an important role in viral replication. Inhibition of their functions should be able to significantly interfere with the replication cycle of the virus, and therefore these key proteins may serve as potential therapeutic targets. The functions of the above viral targets and their corresponding inhibitors have been summarized in the current review. This review provides comprehensive updates of nsp3 and nsp5 inhibitor development and would help advance the discovery of novel anti-viral therapeutics against SARS-CoV-2.
| S-EPMC8382591 | biostudies-literature
Project description:After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential antiviral agents. SARS-CoV-2 3CLpro is essential for processing the viral polyproteins into mature non-structural proteins, making it an attractive target for developing antiviral agents. Here we show that Vitamin K3 screened from the FDA-Approved Drug Library containing an array of 1,018 compounds has potent inhibitory activity against SARS-CoV-2 3CLpro with the IC50 value of 4.78 ± 1.03 μM, rather than Vitamin K1, K2 and K4. Next, the time-dependent inhibitory experiment was carried out to confirm that Vitamin K3 could form the covalent bond with SARS-CoV-2 3CLpro. Then we analyzed the structure-activity relationship of Vitamin K3 analogues and identified 5,8-dihydroxy-1,4-naphthoquinone with 9.8 times higher inhibitory activity than Vitamin K3. Further mass spectrometric analysis and molecular docking study verified the covalent binding between Vitamin K3 or 5,8-dihydroxy-1,4-naphthoquinone and SARS-CoV-2 3CLpro. Thus, our findings provide valuable information for further optimization and design of novel inhibitors based on Vitamin K3 and its analogues, which may have the potential to fight against SARS-CoV-2.
| S-EPMC8064871 | biostudies-literature
Project description:The pandemic, COVID-19, has spread worldwide and affected millions of people. There is an urgent need, therefore, to find a proper treatment for the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent. This paper focuses on identifying inhibitors that target SARS-CoV-2 proteases, PLPRO and 3CLPRO, which control the duplication and manages the life cycle of SARS-CoV-2. We have carried out detailed in silico Virtual high-throughput screening using Food and Drug Administration (FDA) approved drugs from the Zinc database, COVID-19 clinical trial compounds from Pubchem database, Natural compounds from Natural Product Activity and Species Source (NPASS) database and Maybridge database against PLPRO and 3CLPRO proteases. After thoroughly analyzing the screening results, we found five compounds, Bemcentinib, Pacritinib, Ergotamine, MFCD00832476, and MFCD02180753 inhibit PLPRO and six compounds, Bemcentinib, Clofazimine, Abivertinib, Dasabuvir, MFCD00832476, Leuconicine F inhibit the 3CLPRO. These compounds are stable within the protease proteins' active sites at 20ns MD simulation. The stability is revealed by hydrogen bond formations, hydrophobic interactions, and salt bridge interactions. Our study results also reveal that the selected five compounds against PLPRO and the six compounds against 3CLPRO bind to their active sites with good binding free energy. These compounds that inhibit the activity of PLPRO and 3CLPRO may, therefore, be used for treating COVID-19 infection.
| S-EPMC8018918 | biostudies-literature